HSP70 interacts with TRAF2 and differentially regulates TNFα signalling in human colon cancer cells

Abstract

Members of tumour necrosis factor (TNF) family usually trigger both survival and apoptotic signals in various cell types. Heat shock proteins (HSPs) are conserved proteins implicated in protection of cells from stress stimuli. However, the mechanisms of HSPs in TNFα-induced signalling pathway have not been fully elucidated. We report here that HSP70 over-expression in human colon cancer cells can inhibit TNFα-induced NFκB activation but promote TNFα-induced activation of c-Jun N-terminal kinase (JNK) through interaction with TNF receptor (TNFR)-associated factor 2 (TRAF2). We provide evidence that HSP70 over-expression can sequester TRAF2 in detergent-soluble fractions possibly through interacting with TRAF2, leading to reduced recruitment of receptor-interacting protein (RIP1) and IκBα kinase (IKK) signalosome to the TNFR1–TRADD complex and inhibited NFκB activation after TNFα stimuli. In addition, we found that HSP70–TRAF2 interaction can promote TNFα-induced JNK activation. Therefore, our study suggests that HSP70 may differentially regulate TNFα-induced activation of NFκB and JNK through interaction with TRAF2, contributing to the pro-apoptotic roles of HSP70 in TNFα-induced apoptosis of human colon cancer cells.

Apoptotic and necrotic effects of tumour necrosis factor-alpha potentiated with hyperthermia on L929 and tumour necrosis factor-alpha-resistant L929

“…Hsp70 is expressed by almost all the cells and may exert both pro-apoptotic [38,39] and anti-apoptotic [37,40] roles. Through the interaction with TNF receptor (TNFR)-associated factor 2 (TRAF2), Hsp70 differentially regulates TNF-induced activation of NF-kB (antiapoptotic signal) and cJun N-terminal kinase (JNK, apoptotic signal) [36]. Within the cell membrane, specialised microdomains, known as lipid rafts, coordinate various signalling pathways involved in cancer development [41].…”

“…Another possible mechanism by which hyperthermia enhances the antitumour effect of TNF-is the overexpression of heat shock proteins (HSPs) [36]. HSPs are highly conserved proteins which are synthesised to protect cells against the harmful consequences of stress stimuli, including those imposed by heat shock [37].…”

The Ras Signaling Inhibitor LOX-PP Interacts with Hsp70 and c-Raf To Reduce Erk Activation and Transformed Phenotype of Breast Cancer Cells

“…Hsp70 family proteins are highly conserved and have three regions mediating interaction with various proteins, including an ATPase domain in the N-terminal region, a peptide binding domain in the C-terminal region, and an acidic motif (EEVD) at the C terminus. The peptide binding domain of Hsp70 has been reported to bind to PKC␤II, p53, Rictor, apoptosis-inducing factor (AIF), JNK1, TRAF2, TRAF6, Ku70, and MstI (7,11,16,29,37,40,54,58,59). Meanwhile, Hsp70 interacts with Hip, Bag-1, Bax, hYVH1, PARP-1, CD40, and Ask1 via its ATPase domain (3,17,25,26,36,53,64) and with Hop (Hsp70/Hsp90-organizing protein) and CHIP via the EEVD motif (1,12).…”

Interaction of Marek's disease virus oncoprotein Meq with heat-shock protein 70 in lymphoid tumour cells

“…The molecular chaperone Hsp70 has been shown to be involved in diverse cellular functions including neoplastic transformation (Dai et al, 2009;Meimaridou et al, 2009). Hsp70 has also been shown to interact with a number of virus-encoded proteins (Forsman et al, 2008;Lum et al, 1992;Young et al, 2008).…”